PsychoTropical Research - Dr Ken Gillman, Serotonin Syndrome, Mirtazapine, Dual Action Drugs. Antidepressants - Toxicity.

PsychoTropicalResearch, serotonin and serotonin syndrome research.

Antidepressants - Toxicity

Antidepressants - Toxicity

Date Created: 29/11/2000   Last Modified: 17/01/2003   Last Checked: 17/01/2003

There is a widespread assumption that 'new is better' and that all new antidepressants have less side effects and are less toxic in over-dose. In general such views reflect the power of advertising more than they reflect reality. Australian toxicologists are gathering quality prospective data to elucidate such questions. Regrettably, few people access this data, or study it. Some recent data gives a further indication of the type of toxicity associated with venlafaxine, relative to other antidepressants (Whyte, I.M. and A.H. Dawson, Relative toxicity of venlafaxine and serotonin specific reuptake inhibitors in overdose. Journal of Toxicology - Clinical Toxicology, 2001. 39: p. 255).

Analysis of 456 consecutive admissions with antidepressant poisoning to a teaching hospital toxicology service.

  • venlafaxine = 51
  • tricyclic antidepressant (excluding dothiepin) = 172
  • SSRI = 233

Also a separate group; dothiepin = 81-- for comparison of seizure activity (because there is already substantial evidence that dothiepin is much more prone to precipitate seizures).

Odds ratios (95% CIs, p) for specified outcomes

  1. Seizures
    Dothiepin vs TCAs-- OR 3.4; CI (1.0 - 12.0, p = 0.04)
    Venlafaxine vs TCAs-- 4.4 (1.2 – 16.6, p = 0.02)
    SSRIs vs TCAs-- 0.4 (0.1 – 1.7, p = 0.25).
  2. Arrhythmias
    TCAs vs venlafaxine 0.0 (0.0 – 5.1, p = 0.70)
    SSRIs vs TCAs 0.2 (0.0 – 1.9, p = 0.21)
  3. Coma
    Venlafaxine vs TCAs 0.1 (0.0 – 0.6, p = 0.005)
    SSRIs vs TCAs 0.1 (0.0 – 0.2, p < 0.0001)
  4. Prolonged QRS (to >= 100 ms)
    SSRIs vs TCAs 0.3 (0.2 – 0.6, p < 0.0001)
    TCAs vs venlafaxine 0.6 (0.3 – 1.4, p = 0.31)
  5. Admission to ICU
    SSRIs vs TCAs 0.1 (0.1 – 0.2, p < 0.0001)
    venlafaxine vs TCAs 0.5 (0.2 – 1.0, p = 0.051).
  6. Serotonin syndrome
    venlafaxine vs TCAs 35.4 (7.6 – 325.3, p < 0.0001)
    SSRIs vs TCAs 20.4 (5.2 – 174.9, p < 0.0001)

Interpretation

An Odds Ratio (OR) of 1.0 means the event is equally likely in each group compared. So, for serotonin syndrome (6), venlafaxine is about 35 times more likely to cause it than TCAs. The sample size allows the estimation that the minimum difference is 7.6 times, and the maximum 325 times. That means we can be very sure that venlafaxine is at least ten times more like than TCAs to cause SS.

Conclusions

Dothiepin in overdose is more pro-convulsant than any other TCA. There may be an argument for avoiding its use altogether, especially since there is no evidence it is better than other TCAs. These experienced toxicologists advise it is definitely best to avoid both dothiepin and venlafaxine if there is any risk of seizure or suicide.

Venlafaxine in overdose is probably more pro-convulsant than the TCAs (as a group) and possibly even more pro-convulsant than Dothiepin, which has already been shown to be worse than the other TCAs. It is equally likely to produce arrythmias and much more likely to cause serotonin syndrome than TCAs, and perhaps even than SSRIs (the venlafaxine vs SSRI comparison shows a non-significant trend). That is surprising because venlafaxine (in vitro) is the weakest of all the SRIs so this hints at some other mechanism of action for venlafaxine which is as yet unknown.

It will be some time before the numbers allow a comparison of death rates from over-doses of various different new antidepressants. These figures suggest venlafaxine may turn out to be more toxic than the old TCAs; the mechanism may be sodium channel blockade. The property of sodium channel blockade may be responsible for the neuropathic pain relieving abilities of various drugs and may be inextricably linked with this kind of toxicity.

Last thought: is toxicity always 'bad'?

The old expression, 'there's no such thing as a free lunch' is as true in pharmacology as it is in life. Potent and effective drugs often have more side effects. When drugs are used appropriately for serious illnesses (and depression is undoubtedly a serious illness) toxicity in over-dose is not often a major clinical issue; it is the drugs ability to produce remission that is the over-riding consideration. If a particular drug produces a greater response rate, and if the evidence for that is convincing, then it is likely to produce a significant net benefit. Remember that 95% of deaths by suicide are by means other than the antidepressant being taken for treatment of the depressive illness.